Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i>
Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell express...
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MDPI AG
2021-03-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/3/482 |
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| author | Robert J. Huber William D. Kim Sabateeshan Mathavarajah |
| author_facet | Robert J. Huber William D. Kim Sabateeshan Mathavarajah |
| author_sort | Robert J. Huber |
| collection | DOAJ |
| description | Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target proteins, and has been studied extensively in various eukaryotes including fungi, plants, and metazoans. Here, we examine the biological processes influenced by neddylation in the social amoeba, <i>Dictyostelium discoideum</i>, using a well-established inhibitor of neddylation, MLN4924 (pevonedistat). NEDD8, and the target of MLN4924 inhibition, NEDD8-activating enzyme E1 (NAE1), are highly conserved in <i>D. discoideum</i> (Nedd8 and Nae1, respectively). Treatment of <i>D. discoideum</i> cells with MLN4924 increased the amount of free Nedd8, suggesting that MLN4924 inhibited neddylation. During growth, MLN4924 suppressed cell proliferation and folic acid-mediated chemotaxis. During multicellular development, MLN4924 inhibited cyclic adenosine monophosphate (cAMP)-mediated chemotaxis, delayed aggregation, and suppressed fruiting body formation. Together, these findings indicate that neddylation plays an important role in regulating cellular and developmental events during the <i>D. discoideum</i> life cycle and that this organism can be used as a model system to better understand the essential roles of neddylation in eukaryotes, and consequently, its involvement in human disease. |
| first_indexed | 2024-03-10T12:57:41Z |
| format | Article |
| id | doaj.art-08d460b4eb4d4b81b08f322269c0d820 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T12:57:41Z |
| publishDate | 2021-03-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-08d460b4eb4d4b81b08f322269c0d8202023-11-21T11:43:12ZengMDPI AGBiomolecules2218-273X2021-03-0111348210.3390/biom11030482Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i>Robert J. Huber0William D. Kim1Sabateeshan Mathavarajah2Department of Biology, Trent University, Peterborough, ON K9L 0G2, CanadaEnvironmental and Life Sciences Graduate Program, Trent University, Peterborough, ON K9L 0G2, CanadaDepartment of Pathology, Dalhousie University, Halifax, NS B3H 4R2, CanadaNeddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target proteins, and has been studied extensively in various eukaryotes including fungi, plants, and metazoans. Here, we examine the biological processes influenced by neddylation in the social amoeba, <i>Dictyostelium discoideum</i>, using a well-established inhibitor of neddylation, MLN4924 (pevonedistat). NEDD8, and the target of MLN4924 inhibition, NEDD8-activating enzyme E1 (NAE1), are highly conserved in <i>D. discoideum</i> (Nedd8 and Nae1, respectively). Treatment of <i>D. discoideum</i> cells with MLN4924 increased the amount of free Nedd8, suggesting that MLN4924 inhibited neddylation. During growth, MLN4924 suppressed cell proliferation and folic acid-mediated chemotaxis. During multicellular development, MLN4924 inhibited cyclic adenosine monophosphate (cAMP)-mediated chemotaxis, delayed aggregation, and suppressed fruiting body formation. Together, these findings indicate that neddylation plays an important role in regulating cellular and developmental events during the <i>D. discoideum</i> life cycle and that this organism can be used as a model system to better understand the essential roles of neddylation in eukaryotes, and consequently, its involvement in human disease.https://www.mdpi.com/2218-273X/11/3/482neddylationNEDD8<i>Dictyostelium discoideum</i>social amoebaMLN4924post-translational modification |
| spellingShingle | Robert J. Huber William D. Kim Sabateeshan Mathavarajah Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> Biomolecules neddylation NEDD8 <i>Dictyostelium discoideum</i> social amoeba MLN4924 post-translational modification |
| title | Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> |
| title_full | Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> |
| title_fullStr | Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> |
| title_full_unstemmed | Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> |
| title_short | Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in <i>Dictyostelium discoideum</i> |
| title_sort | inhibiting neddylation with mln4924 suppresses growth and delays multicellular development in i dictyostelium discoideum i |
| topic | neddylation NEDD8 <i>Dictyostelium discoideum</i> social amoeba MLN4924 post-translational modification |
| url | https://www.mdpi.com/2218-273X/11/3/482 |
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